Control of inflammation in periodontal regeneration is a major public health problem. Approximately 50% of the population of the United States has some form of periodontal disease and tissue engineering procedures cannot completely restore hard and soft tissues. Control of endogenous inflammation is an absolute requirement for tissue engineering success. There is a critical need for new therapeutics in regeneration that control local inflammation. The long-term goal of this R01 proposal is to utilize natural resolution of inflammation to control local inflammation and accelerate regeneration. Resolvins mediate resolution of inflammation facilitating periodontal regeneration and a return to homeostasis. Our group introduced the novel concept that inflammatory disease may result from a failure of active resolution. Accumulating evidence suggests that agonists of endogenous resolution programs may be the best approach to control inflammation in periodontal regeneration and reconstruction. The Central Hypothesis is that resolution of inflammation pathways and mediators can be harnessed to control inflammation in periodontal tissues enabling regeneration and reconstruction. We have demonstrated that delivery of lipoxins and resolvins greatly enhances tissue regeneration by control of inflammation. Resolvins also have actions beyond control of neutrophils including receptor mediated control of osteoclast and osteoblast function in wound healing and bone regeneration. We will identify key endogenous control mechanisms for bone formation induced by RvE1 using specific RvE1 receptor knock-out (KO) and receptor over-expressing transgenic mice, determine the basis for bone cell responses to RvE1 by elucidation of signal anabolic pathways that promote osteoblast mediated bone formation and limit osteoclast activity, and unravel the complexities of lipid mediator synergy and characterize hetero- specific resolution agonist amplification by determining pro and anti-inflammatory lipid mediator profiles induced by RvE1. Results from these studies will advance our knowledge of mechanisms in natural resolution of inflammation in tissue regeneration to develop novel bioengineering-based strategies targeted for periodontal regeneration. Our experienced research team consists of experts in cell biology, pharmacological biochemistry, animal models and periodontal regeneration that are well positioned to carry out this project.